Effect Of Cortisol On Event Related Potential Correlates Of Recollection In Healthy Men R.H. McAllister-Williams 1 and M.D. Rugg Department of Psychiatry, University of Newcastle, Newcastle upon Tyne, UK 2 - Institute of Cognitive Neuroscience, University College London, London, UK uV 1.34uV 3.84uV -0.15uV 1.97uV -2.16uV 0.59uV 5.17uV3.28uV -1.46uV 1.17uV -3.39uV Placebo Cortisol Introduction l Depression is associated with high cortisol and impaired neuropsychological function 1 l Healthy subjects administered glucocorticoids have impaired memory 2,3,4 l Hypotheses F Cortisol administration will reversibly impair source memory (recollection) F This impairment will be associated with attenuated recollection-related ERP activity, especially in right frontal cortex. FZF5 F6 FP2 FP1 T8 C3 C5 TP7 O1 PZ O2 TP8 CZT7 C6 C4 l Study phase F 40 low frequency words (1-7/million) – 20 in male voice, 20 in female voice F Repeat word, then state “pleasant”/“unpleasant”, “active”/“passive” decision based on sex of voice l Test phase (after delay of 5 minutes) F 80 words presented visually F Initial old/new judgement F If old then male/female judgement l Study-test-study-test design l Significant effect of visit on source judgement accuracy(F(1,12) = 9.74, p < 0.01) l Cortisol significantly reduced recognition accuracy on visit 2 (t(6) = 2.62, p < 0.025) l Cortisol significantly speeded response times(F(1,12) = 9.58, p < 0.01) l Words presented on screen for 500 ms l First response ASAP when see word l Second response ASAP when see “?” presented 1000 ms after 1st response l Next trial 1400 ms after 2nd response l EEG recorded from 100ms prior to word presentation to 1400ms post word Methods l 2 way cross over, double blind, random and balanced order experiment in 14 healthy male volunteers l 20mg hydrocortisone/placebo for 7 days F commencing evening of day 1 F finishing morning of day 8 F ERP recordings in afternoon of day 8 l 24 hour urinary free cortisol from a.m. day 7 to a.m. day 8 Behavioural Analysis l Responses categorised as: F ‘Correct rejections’ (CR) - correctly identified new items F ‘False alarms’ (FA) - new items identified as old F ‘Hits’ (H) - correctly identified old items F ‘Misses’ (M) - old items identified as new F ‘Hit/Hits’ (HH) - old items with correct sex judgement F ‘Hit/Misses’ (HM) - old items with incorrect sex judgement l Main focus of interest F recognition probability (pH - pFA) F source judgement probability (pHH/H) ERP Analysis l Words presented on screen for 500 ms l First response ASAP when see word l Second response ASAP when see “?” presented 1000 ms after 1st response l Next trial 1400 ms after 2nd response l EEG recorded from 100ms prior to word presentation to 1400ms post word l The effect of cortisol began around 400 ms after stimuli presentation and was long lasting l The effect of cortisol on correct rejection ERPs was widespread across the scalp (Fig. 4A and D) l There was a relative lack of effect of cortisol on ERPs to hit/hits at frontal sites (Fig 4B and D) l This differential effect of cortisol depending on the nature of the stimuli led to an apparent reduction in the frontal ‘old/new’ effect (Fig 4C and 5) l Sphericalsplinemaps illustrating the scalp topography of the differences between ERPs to hit/hits and correct rejections following placebo and cortisol l Topographic analysis revealed significant drug by site interactions between 500 and 800 ms (F(5.2,67.4) = 2.90, p < 0.025) and 1100 and 1400 ms (F(5.2,68.2) = 2.38, p < 0.05) F Analysis conducted on all sites on HH-CR amplitude difference re- scaled to remove global differences in amplitude l No effect of cortisol on left parietal or right frontal ‘old/new’ effects F subsidiary analysis on lateral parietal sites ms and lateral frontal sites ms F significant hemisphere by site interactions unmodified by an interaction with drug. Conclusions l Chronic administration of cortisol to healthy subjects causes an impairment in verbal recognition memory and a speeding of response times l The ERP correlates of episodic memory are markedly affected by cortisol F cortisol increased the ERPpositivitywith a differential effect on ERPs elicited by correct rejections and hit/hits F These effects were additive with the ‘left parietal’ and ‘right frontal’ old/new effects l The hypothesis of attenuated old/new component(s) is not supported F Cortisol modulates neural generators distinct from those responsible for the old/new ERP effect References 1.McAllister-Williams R.H., Ferrier I.N., and Young A.H. (1998) Mood and neuropsychological function in depression: the role of corticosteroids and serotonin. Psychol. Med. 28, Young A.H., Sahakian B.J., Robbins T.W., and Cowen P.J. (1999) The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Psychopharm. 145, Newcomer J.W., Selke G., Melson A.K., Hershey T., Craft S., Richards K., and Alderson A.L. (1999) Decreased memory performance in healthy humans induced by stress-level cortisol treatment.Arch. Gen. Psychiatry 56, de Quervain D.J.F., Roozendaal B., Nitsch R.M., McGaugh J.L., and Hock C. (2000) Acute cortisone administration impairs retrieval of long-term declarative memory in humans.Nature Neurosci. 3, Wilding E.L. and Rugg M.D. (1996) An event-related potential study of recognition memory with and without retrieval of source.Brain 119, Acknowledgements Work supported by the Medical Research Council (UK) via aClinican Scientist Fellowship to RHMcAW. MDR is supported by the Wellcome Trust AB CD l EEG sampling time-locked to onset of each word at test F 29 scalp electrodes (red + blue) F referenced to left mastoid, re- referenced off-line to linked mastoids F band width Hz F blink corrected using VEOG F Post-hoc analysis used 6 red sites to examine ant/post and left/right differences l ERPs following placebo demonstrate the same ‘old/new’ effects as previously reported 5 F Significant response (CRvsHH) by ant./post. by hemisphere interaction ms post stimuli (F(1,13) = 13.13, p < 0.005) due to left parietal positivityof ERPs for hit/hits relative to correct rejections F Significant response(CRvsHH) by ant./post. by hemisphere interaction ms post stimuli (F(1,13) = 15.70, p < 0.005) due to right frontal positivity of ERPs for hit/hits relative to correct rejections l Cortisol significantly modulated memory-related ERP effects F Significant drug by response (CRvsHH) by ant./post. interaction ms post stimuli (F(1,13 = 7.42, p < 0.025) F Significant drug by response (CRvsHH) by ant./post. interaction ms post stimuli (F(1,13 = 5.02, p < 0.05) F Significant drug by response (CRvsHH) interaction ms post stimuli (F(1,13 = 6.12, p < 0.05)